The Role of the General Practitioner in Managing Age-Related Hearing Loss: A Scoping Review.

Purpose The purpose of this review was to examine the research activity relating to the role of the general practitioner (GP) in managing age-related hearing loss in older adults. Method A literature search of peer-reviewed journal articles published in English was conducted in online bibliographic databases using multiple variations of the keywords "general practitioner" and "hearing." Results The search strategy identified 3,255 articles. The abstracts of all articles were screened with 124 full-text records subsequently assessed for eligibility. Forty-nine articles met the inclusion criteria and were included in this review. Conclusions For people with hearing loss, the GP can play an instrumental role in guiding appropriate and timely choices for addressing hearing concerns. There are a range of quick, easy, and sensitive methods available to GPs to assist the objective evaluation of hearing. The evidence suggests that implementing hearing screening programs targeting older adults will increase rates of hearing loss detection and subsequently increase the number of patients receiving hearing loss intervention. Education and training appear key to improving GPs' screening, management, and referral of patients with hearing loss in the primary health care setting.

Antisense Oligonucleotides Targeting Angiogenic Factors as Potential Cancer Therapeutics.

Cancer is one of the leading causes of death worldwide, and conventional cancer therapies such as surgery, chemotherapy, and radiotherapy do not address the underlying molecular pathologies, leading to inadequate treatment and tumor recurrence. Angiogenic factors, such as EGF, PDGF, bFGF, TGF-ß, TGF-α, VEGF, endoglin, and angiopoietins, play important roles in regulating tumor development and metastasis, and they serve as potential targets for developing cancer therapeutics. Nucleic acid-based therapeutic strategies have received significant attention in the last two decades, and antisense oligonucleotide-mediated intervention is a prominent therapeutic approach for targeted manipulation of gene expression. Clinical benefits of antisense oligonucleotides have been recognized by the U.S. Food and Drug Administration, with full or conditional approval of Vitravene, Kynamro, Exondys51, and Spinraza. Herein we review the scope of antisense oligonucleotides that target angiogenic factors toward tackling solid cancers.

Feeling supported and abandoned: mixed messages from attendance at a rural community cardiac rehabilitation program in Australia.

PURPOSE: In 2010, the Healthy Heart (HH) community-based cardiac rehabilitation program was offered at Latrobe Community Health Service in rural Victoria, Australia. The 8-week program, based on National Heart Foundation guidelines, consisted of exercise sessions; health education on diet, stress, and smoking cessation; and behavioral change strategies. Participants were also informed about local community exercise opportunities. A program evaluation was conducted in 2011 to assess whether the content of the program was meeting the needs of participants and to identify what suggestions they had for improvement. METHODS: Eighteen patients had completed the HH program in 2010. Eight of these participants, 7 men and 1 woman, volunteered to take part in a focus group. Conventional content analysis was used to identify and group the common themes that emerged from the focus group discussions. RESULTS: Three themes were identified that reflected the participant experiences of attending the HH program. The first, "recovering confidence," described participant responses to the content of the sessions. The second, "putting it into practice," referred to their comments about taking responsibility for making lifestyle changes. The third, "feeling abandoned," emerged from the reported difficulty participants expressed about maintaining motivation for change after program completion. CONCLUSION: Participants rated the HH program as very successful by objective measures. However, they reported struggling to maintain self-management strategies postprogram. There is clearly a need to develop strategies that support cardiac rehabilitation participants over the longer-term.

RNA splicing manipulation: strategies to modify gene expression for a variety of therapeutic outcomes.

Antisense oligomers initially showed promise as compounds to modify gene expression, primarily through RNaseH induced degradation of the target transcript. Expansion of the field has led to new chemistries capable of invoking different mechanisms, including suppression of protein synthesis by translational blockade and gene silencing using short interfering RNAs. It is now apparent that the majority of the eukaryotic genome is transcribed and non-protein coding RNAs have been implicated in the regulation of gene expression at many levels. This review considers potential therapeutic applications of antisense oligomers to modify gene expression, primarily by interfering with the process of exon recognition and intron removal during gene transcript splicing. While suppression of gene expression will be necessary to address some conditions, it is likely that antisense oligomer splice modification will have extensive clinical application. Pre-mRNA splicing is a tightly co-ordinated, multifactorial process that can be disrupted by antisense oligomers in a highly specific manner to suppress aberrant splicing, remove exons to by-pass nonsense or frame-shifting mutations or influence exon selection to alter spliceoform ratios. Manipulation of splicing patterns has been applied to a diverse range of conditions, including b-thalassemia, Duchenne muscular dystrophy, spinal muscular atrophy and certain cancers. Alternative exon usage has been identified as a major mechanism for generating diversity from a limited repertoire of genes in higher eukaryotes. Considering that the majority of all human primary gene transcripts are reportedly alternatively spliced, intervention at the level of pre-mRNA processing is likely to become increasingly significant in the fight against genetic and acquired disorders.

Successful treatment of venous stasis ulcers with combination compression therapy and pulsed radio frequency energy in a patient scheduled for amputation.

BACKGROUND: Venous ulcers are a frequent complication of chronic venous insufficiency. Compression therapy remains the mainstay of conservative treatment, as many patients are not candidates for surgical intervention. CASE: A 78-year-old man was referred to our Preservation-Amputation Care and Treatment for management of 3 venous stasis ulcers on the front of the left lower leg. Multiple comorbid conditions and his generally poor health rendered him a poor candidate for surgical reperfusion In addition, his right leg was amputated approximately 3 years before, and he was nonweight bearing on the remaining left leg. In order to heal these venous stasis ulcers and preserve his limb, Mr A underwent treatment with a combination of compression therapy and pulsed radio frequency energy. CONCLUSION: Compression therapy plus pulsed radio frequency energy led to healing of his venous leg ulcers and avoided amputation of the affected limb. This treatment is currently being evaluated in other patients with chronic venous insufficiency and ulceration.

Splice modification to restore functional dystrophin synthesis in Duchenne muscular dystrophy.

In little more than a decade, induced exon skipping as a therapy to treat Duchenne muscular dystrophy (DMD) has progressed from a concept tested in vitro, to pre-clinical evaluation in mouse and dog models, and recent completion of Phase I clinical trials in man. There is no longer any doubt that antisense oligomers can redirect dystrophin gene processing and by-pass protein truncating mutations after direct injection into muscle. Proof-of-concept has been demonstrated in human dystrophic muscle, with trials in Leiden and London showing that two different oligomer chemistries can restore the reading-frame in selected DMD patients by excising dystrophin exon 51. Systemic delivery of both oligomer types into DMD patients has commenced with promising results but it remains to be established if this therapy will have measurable clinical benefits. Targeted removal of exon 51 will only be directly applicable to about one in ten DMD individuals, and the immediate challenges include development of appropriate and effective delivery regimens, and extending splice-switching therapies to other dystrophin gene lesions. The success of induced exon skipping has spawned a number of "fusion therapies", including vector-mediated dystrophin exon skipping and ex vivo viral delivery of splice-switching antisense molecules into myogenic stem cells, followed by implantation, which may address long term oligomer delivery issues. This review summarizes the pivotal events leading to the completion of the first proof-of-concept trials and speculates on some of the scientific, ethical, regulatory and commercial challenges facing targeted exon skipping for the treatment of DMD.

Where are older workers with chronic conditions employed?

OBJECTIVE: To determine which industries and occupational groups are associated with employment of older workers with chronic work-limiting health conditions in Australia. DESIGN AND PARTICIPANTS: Analysis of data from the 2005 National Health Survey for 4228 workers aged 45-64 years. MAIN OUTCOME MEASURES: Rate of employment by industry and occupation of older workers with specific chronic conditions. RESULTS: Compared with the reference industry of property and business services, workers in the retail trade industry were found to be more likely to suffer from musculoskeletal conditions (relative risk ratio [RRR], 1.56; 95% CI, 1.04-2.36), while those in health and community services had higher rates of cardiovascular disease (RRR, 2.17; 95% CI, 1.11-4.24). Compared with the reference occupation group of professionals, managers and administrators were less likely to suffer neoplasms (RRR, 0.25; 95% CI, 0.07-0.97). Similar rates of chronic disease were seen across other occupations. CONCLUSION: Increasing rates of chronic health conditions are unlikely to have an even impact across the workforce, as the rate of employment of older workers with these conditions varies between industries.

Redirecting splicing to address dystrophin mutations: molecular by-pass surgery.

Mutations in the dystrophin gene that prevent synthesis of a functional protein lead to Duchenne muscular dystrophy (DMD), the most common serious childhood muscular dystrophy. The major isoform is produced in skeletal muscle and the size of the dystrophin gene and complexity of expression have posed great challenges to the development of a therapy for DMD. Considerable progress has been made in the areas of gene and cell replacement, yet it appears that any potential therapy for DMD is still some years away. Other approaches are being considered, and one that has generated substantial interest over the last few years is induced exon skipping. Antisense oligonucleotides have been used to block abnormal splice sites and force pre-mRNA processing back to the normal patterns. This approach is re-interpreted to address the more common dystrophin mutations, where normal splice sites are targeted to induce abnormal splicing, resulting in specific exon exclusion. Selected exon removal during processing of the dystrophin pre-mRNA can by-pass nonsense mutations or restore a disrupted reading frame arising from genomic deletions or duplications. Attributes of the dystrophin gene that have hampered gene replacement therapy may be regarded as positive features for induced exon skipping, which may be regarded as a form of by-pass surgery at the molecular level. In humans, antisense oligonucleotides have been more generally applied to down-regulate specific gene expression, for the treatment of acquired conditions such as malignancies and viral infections. From interesting in vitro experiments several years ago, the dystrophin exon-skipping field has progressed to the stage of planning for clinical trials.

RNA splicing manipulation: strategies to modify gene expression for a variety of therapeutic outcomes.

Antisense oligonucleotides initially offered great hope as specific compounds to modify gene expression, primarily through RNaseH induced degradation of the target transcript. Expansion of the field led to new chemistries capable of invoking different mechanisms, including suppression of protein synthesis by translational blockade, and there is now a major interest in downregulation of gene expression using short interfering RNAs to induce RNA silencing. Naturally occurring microRNAs have been implicated in the regulation of gene expression. This review considers examples of antisense oligonucleotides redirecting the process of exon recognition and intron removal during gene transcript splicing. While suppression of gene expression is necessary to address some conditions, it appears likely that there may be many more clinical applications for antisense oligonucleotides in re-directing splicing patterns. Pre-mRNA splicing is a tightly co-ordinated, multifactorial process, which can be disrupted by antisense oligonucleotides in a highly specific manner, allowing either suppression of aberrant splicing, by-pass of nonsense or frame-shifting mutations or alteration of spliceoform ratios. Manipulation of splicing patterns has been applied to a diverse range of conditions, including beta-thalassemia, Duchenne muscular dystrophy, spinal muscular atrophy and certain cancers. Alternative exon usage has been identified as a major mechanism for generating diversity from a limited repertoire of genes in higher eukaryotes. Considering that up to 75% of all human primary gene transcripts are reported to be alternatively spliced, intervention at the level of pre-mRNA processing is likely to become increasingly significant in the fight against genetic and acquired disorders.